Abnormalities of stem cell function and/or the destruction of stem cells lead to an olfactory epithelium (OE) that remains olfactory (including a full apical lining composed of sustentacular cells), but one that has no neurons (OSNs), no globose basal cells (GBCs), and no ongoing neurogenesis - a condition that we term neurogenic exhaustion. We have developed a mouse model based on the expression of Diptheria toxin subunit A (DTA) in OMP-expressing mature OSNs that causes a tetracycline-reversible abbreviation of normal neuronal life-span and causes proliferation to accelerate at first, but then eventually dissipate. Aim 1 proposes experiments to understand when and how GBC stem cell failure develops by analyzing the GBC population as a function of age, as well as its capacity to generate olfactospheres in culture and engraft after transplantation - both of the latter phenomena assay the functional status of the progenitor population. Aim 2 shifts its focus to a second type of olfactory stem cell called horizontal basal cells (HBCs). Unlike GBCs, the HBCs persist in aneuronal OE, but are not functioning as multipotent progenitors/stem cells as they can do when the epithelium is directly injured and more than just neurons are dying. The HBCs will be activated out of their dormancy by a conditional knock-out strategy aimed at the transcription factor p63. We will test whether the GBCs that originate from the HBCs will persist and repopulate the epithelium. Aim 3 will assay whether restoration of the neuronal population, in this case by taking advantage of the reversibility of our DTA-driven experimental model and stopping the premature death of the neurons, results in correct reinnervation of the olfactory bulb. The experiments in Aim 3 will establish whether it is realistic to expect that the rejuvenation of the stem and progenitor populations and the reestablishment of neuronal input to the CNS can restore appropriate function. Currently, the complete lack of therapeutic options for patients with olfactory disease provides a strong justification for pursuing this research.